Nutraceuticals are a class of natural product that is attracting increasing attention. Nutraceuticals refer to a food or food component claimed to human health benefits. Nutraceuticals more specifically relate to individual chemicals present in foods and are commonly marketed as dietary supplements. Examples of nutraceuticals include amino acids and amino acid derivatives such as sarcosine, nicotinic acid, pantothenic acid, and gamma-linoleic acid; and purine derivatives, such as xanthines.
Dietary polyphenols are one category of nutraceuticals and represent a wide variety of compounds that occur in fruits, vegetables, wine, tea, extra virgin olive oil, chocolate and other cocoa products. They are mostly derivatives and/or isomers of flavones, isoflavones, flavonols, catechins, and phenolic acids, and exhibit many biologically significant functions, such as protection against oxidative stress, and degenerative diseases. Experimental data indicate that most of these biological actions can be attributed to their intrinsic antioxidant capabilities, and dietary polyphenols are the most abundant antioxidants in human diets. Dietary polyphenols may offer an indirect protection by activating endogenous defense systems and by modulating cellular signaling processes such as nuclear factor-kappa B (NF-κB) activation, activator protein-1 (AP-1) DNA binding, glutathione biosynthesis, phosphoinositide 3 (PI3)-kinase/protein kinase B (Akt) pathway, mitogen-activated protein kinase (MAPK) proteins [extracellular signal-regulated protein kinase (ERK), c-jun N-terminal kinase (JNK) and P38] activation, and the translocation into the nucleus of nuclear factor erythroid 2 related factor 2 (Nrf2) (Han et al. 2007).
Additionally, certain nutraceuticals, namely EGCG and caffeine, have been shown to reduce beta-amyloid levels and plaque formation in transgenic mouse models of Alzheimer's disease (AD). AD is a devastating neurodegenerative disease that currently affects an estimated 4.5 million Americans, costing the United States more than $100 billion annually. Finding a treatment that could delay onset by five years could reduce the number of individuals with AD by nearly 50 percent after 50 years. The nutraceutical quercetin has been reported to have therapeutic effects against neurodegenerative disease in various animal models.
The widespread distribution of flavonoid and other nutraceuticals means that they are ingested in significant quantities by animals. Furthermore, their variety, their relatively low toxicity compared to, for example, alkaloids, and their biological activity means that consumers, food manufacturers, nutraceutical manufacturers, and pharmaceutical companies have become interested in flavonoids for their medicinal properties.
Nutraceuticals can be prepared so as to have a variety of different chemical forms including chemical derivatives or salts. Such nutraceuticals can also be prepared to have different physical forms. For example, the nutraceuticals may be amorphous, may have different crystalline polymorphs, or may exist in different solvation or hydration states. By varying the form of a nutraceutical, it is possible to vary the physical properties thereof. For example, crystalline polymorphs typically have different solubilities from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph. Pharmaceutical polymorphs can also differ in properties such as shelf-life, bioavailability, morphology, vapour pressure, density, colour, and compressibility. Accordingly, variation of the crystalline state of a nutraceutical is one of many ways in which to modulate the physical properties thereof.
A co-crystal is a multiple component crystal containing two or more non-identical molecules in which all components are solid under ambient conditions (i.e. 22° Celsius, 1 atmosphere of pressure) when in their pure form. The components comprise a target molecule (i.e., a nutraceutical) and a molecular co-crystal former that coexist in the co-crystal at the molecular level within a single crystal.
Co-crystals that comprise two or more molecules (co-crystal formers) (Almarsson et al., 2004) that are solids under ambient conditions represent a long-known class of compounds (see Wohler, 1844). However, co-crystals remain relatively unexplored. A Cambridge Structural Database (CSD) (Allen et al., 1993) survey reveals that co-crystals represent less than 0.5% of published crystal structures. Nevertheless, their potential impact upon pharmaceutical (e.g., nutraceutical) formulation (Vishweshwar et al., 2006; Li et al., 2006; Remenar et al., 2003; and Childs et al., 2004) and green chemistry (Anastas et al., 1998) is of topical and growing interest. In particular, the fact that all co-crystal components are solids under ambient conditions has important practical considerations because synthesis of co-crystals can be achieved via solid-state techniques (mechanochemistry)(Shan et al., 2002), and chemists can execute a degree of control over the composition of a co-crystal since they can invoke molecular recognition, especially hydrogen bonding, during the selection of co-crystal formation. Those features distinguish co-crystals from solvates which are another broad and well-known group of multiple component compounds. Solvates are much more widely characterized than co-crystals (e.g., 1652 co-crystals are reported in the CSD versus 10,575 solvates; version 5.27 (May 2006) 3D coordinates, R<0.075, no ions, organics only).
Whereas solid-state organic synthesis represents a well-established area of research (Tanaka et al., 2003; Tanaka et al., 2000; Kaupp et al., 2005), co-crystal controlled solid-state synthesis has been limited to photodimerizations or photopolymerizations (MacGillivray et al., 2000; Fowler et al., 2000) and nucleophilic substitution (Etter et al., 1989). In the case of photodimerizations or photopolymerizations, one co-crystal former typically serves to align or “template” the reactant, which is the other co-crystal former. In the case of the nucleophilic substitution, both co-crystal formers are reactants; although there are examples of solid-state reactions in which the reactive moieties are in the same molecule and therefore generate polymeric structures (Foxman et al., 2000).
It would be advantageous to have new forms of nutraceuticals that have improved properties, in particular, as oral formulations. Specifically, it is desirable to identify improved forms of nutraceuticals that exhibit significantly improved properties including increased aqueous solubility and stability. Further, it is desirable to improve the processability, or preparation of pharmaceutical formulations. For example, needle-like crystal forms or habits of nutraceuticals can cause aggregation, even in compositions where the nutraceutical is mixed with other substances, such that a non-uniform mixture is obtained. It is also desirable to increase or decrease the dissolution rate of nutraceutical-containing pharmaceutical compositions in water, increase or decrease the bioavailability of orally-administered compositions, and provide a more rapid or more delayed onset to therapeutic effect. It is also desirable to have a form of the nutraceutical which, when administered to a subject, reaches a peak plasma level faster or slower, has a longer lasting therapeutic plasma concentration, and higher or lower overall exposure when compared to equivalent amounts of the nutraceutical in its presently-known form. The improved properties discussed above can be altered in a way which is most beneficial to a specific nutraceutical for a specific therapeutic effect.